16,17-seco-delta 4,9(10) and-delta 4,9(10),11 steroids

ABSTRACT

THE NOVEL 16,17-SECOESTRA-4,9(10)-DIENE, 16,17-SECOESTRA-4,9,(10),11-TRIENE, 16,17-SECOGONA-4,9(10)-DIENE AND 16,17-SECOGONA-4,9(10)-TRIENE COMPOUNDS AND THE 14BISOMERS THEREOF USEFUL AS ANTIANDROGENIC AGENTS, AND METHODS FOR THEIR PREPARATION.

Patented June 25, 1974 3,819,686 16,17-SECO-A AND -A STEROIDS PierreCrabbe, Mexico City, Mexico, and John A. Ed-

wards and John H. Fried, Los Altos, Calif., assignors to Syntex (U.S.A.)Inc., Palo Alto, Calif. No Drawing. Filed May 12, 1971, Ser. No. 142,762Int. Cl. C07c 49/56, 69/14, 69/24, 69/74, 69/78 US. Cl. 260-488 B 20Claims ABSTRACT OF THE DISCLOSURE The novell6,l7-sec0estra-4,9(10)-diene, 16,17-secoestra-4,9( 10) ,1 l-triene,16,17-secogona-4,9(10)-diene and 16,17-secogona-4,9(10)-triene compoundsand the 14?- isomcrs thereof useful as antiandrogenic agents, andmethods for their preparation.

The present invention relates to novel 16,17-seco steroids of theestrane and gonane series.

More particularly, this invention relates to certain novel 16, 17-secoestra-4,9 10) -dienes, 16,17-secoestra-4, 9(l0),11-trienes and the13-a1kyl-gonadiene and gonatriene derivatives thereof.

These compounds are represented by the formula:

thereof, or a hydroxylated hydrocarbon radical represented by theformulas:

(3 H- lower alkyl lower alkyl phenyl -O H lower alkyl 0 loweralkyl andthe conventionally hydrolyzable esters and ethers thereof,

R represents lower alkyl;

R and R represent hydrogen or methyl, provided that R is methyl when Ris methyl, and Z is a carbon-carbon single bond or a carbon-carbondouble bond.

These compounds have asymmetric carbon atoms and the varioussteroisomers are included within the scope of this invention.

The term lower alkyl as used herein refers to straight or branched alkylgroups containing up to 4 carbon atoms,

e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like. 1

The term conventional hydrolyzable esters and ethers" as used hereinrefers to hydrolyzable carboxylic ester and other groups knownconventionally in the art. These hydrolyzable carboxylic esters arederived from both substituted and unsubstituted hydrocarbon carboxylicacids. These acids can be completely saturated or possess varyingdegrees of unsaturation (including aromatic), can be of straight chain,branched chain, or cyclic structure, and preferably contain from 1 to 12carbon atoms. In addition, they can be substituted by functional groups,for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxycontaining up to 12 carbon atoms,

nitro, amino, halogeno, and the like, attached to the hydrocarbonbackbone chain. Typical ester groups include acetate, propionate,butyrate, trimethylacetate, valerate, methylethylacetate, caproate,t-butylacetate, 3-mehylpentanoate, enanthate, caprylate,trimethylacetate, pelargonate, decanoate, undecenoate, benzoate,phenylacetate, diphenylacetate, cyclopentylpropionate, methoxyacetate,aminoacetate, diethylaminoacetate, trichloroacetate,fi-chloropropionate, bicyclo-[2.2.2]-octane-1 carboxylate, adamantoate,and the like. Typical ether groups are methyl ether, ethyl ether,cyclopentyl ether, cyclohexyl ether, propyl ether, tetrahydropyran-2-ylether, tetrahydrofuran-2-yl ether, 4'-methoxy-tetrahydropyran-4'-ylether, propyl ether, and the like.

The compounds of the present invention are valuable pharmaceuticalagents possessing anti-androgenic activity. They are of particularutility for the treatment of hyperandrogenic conditions, such as acne,prostatic hypertrophy, hirsutism in the female, seborrheic dermatitisand the like.

The compounds of the present invention are obtained by a processillustrated by the following reaction sequence:

i R2 R7 i .Rl {wvCzHg gMNCgH H H Ra a CH: C H CH3 0 H W 2 a W 2 s O: (VI

R3 R1 I Jfl u-Rl -wC H5 MNCgHs wherein R and R have the above-indicatedmeaning; the wavy lines at C-14 indicate the a or p configuration (eachand mixtures) for the hydrogen atom and the ethyl group at saidposition. I,

In practicing the process illustrated above a 3-keto-16, 17-secoestr-510)-cue, 3-keto-16,17-secogon-5( 10)-cue or the hip-isomers thereof istreated with bromine in pyridine or preferably with pyridiniumperbromide hydrobromide in pyridine solution, to produce thecorresponding A compound of formula II. The amount of pyridiniumperbromide hydrobromide may 'vary between approximately 1 toapproximately 10 molar equivalents of the reagent, preferably about 1.1molar equivalents, using a large excess of pyridine as solvent. Thereaction is carried out at a temperature comprised between --l0 C. androom temperature, for a period of time of the order of one to severalhours. Lower temperatures are also operative, however the reaction isslower. Similarly, temperatures higher than room temperature are alsooperative, but tend to produce in some cases undesirable by-products.

Treatment of a A compound (II) with acetyl chloride in a lower alcoholsuch as methanol or ethanol affords the corresponding M isomer ('III)which upon reaction with a quinone, using particularly 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in dioxane solution, affords theestra-4,9(10),ll-triene or l3-alky1-gona-4,9(10),11- tr'iene compound(IV) or the 14fl-isomers thereof.

In the case of using a free 17-hydroxylated compound as startingmaterial, it is advisable to protect said group prior to the reactionwith acetyl chloride, by conventional esterification or by formation ofthe tetrahydropyranyl-ether, hydrolyzing the protecting group once the A-triene has been formed. Similarly, it is preferred to use an ester of a17-carboxylic acid rather than the free acid.

The reaction of the A -diene with acetyl chloride is carried out underanhydrous conditions at low temperature between -20 to C., for a periodof time of the order of 30 minutes to 2 hours, preferably for about 45minutes. This reaction can be followed by ultraviolet spectrummeasurements of aliquots taken every 10 minutes. When the reaction iscomplete, which is followed by the change of the ultraviolet spectrumfrom 308 III/L to 240 m the product is isolated by extraction with asolvent non-miscible with water. The amount of acetyl chloride used isnot critical, however, it is preferred to use at least one molarequivalent per mol of diene; particularly good results are obtainedusing equal amounts of the steroidal compound and acetyl chloride.

The A -diene is unstable and isomerizes back to the A starting diene;therefore, it is recommended to carry out the next step reaction withquinone right after the isolation of intermediae (III). The A -diene istreated with an excess of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone indioxane solution using preferably from about 2 to about 4 molarequivalents of the quinone per mol of starting material. Thisdehydrogenation is conducted at room temperature for a period of time ofbetween approximately 3 to approximately 20 hours. The reaction can alsobe followed by ultraviolet spectrum measurements of aliquots taken everyhour until the band of 240 m disappears, changing the absorption to 232and 338 my, to afford the compounds of formula IV.

The product is isolated from the reaction mixture by conventionaltechniques, e.g. by separation of the hydroquinone formed during thereaction by decantation or filtration, evaporation of the filtrate todryness and purification of the residue by chromatography on alumina.

When a 17-acyloxylated compound is used and a free 17-hydroxy compoundis desired, the acyloxy group is hydrolyzed by conventional treatmentwith base. When the l7-hydroxy group has been protected as atetrahydropyranyl ether the protecting group can be hydrolyzed by acidtreatment, for example, by treatment with hydrochloric acid in methanolsolution.

The 17-hydroxylated compounds of formulas II and IV lower alkyl (R =CHa-O H, C H-lower alkyl, C or boxylic acid anhydrides in benzenesolution and in the presence of an acid catalyst such asp-toluene-sulfonic acid or with a mixture of a carboxylicacid-carboxylic anhydride in the presence of an acid catalyst for thecompounds having tertiary hydroxyl groups.

Etherification is also carried out by conventional techniques. Thus,reaction with dihydropyran, dihydrofuran or4-methoxy-S,6dihydro-2H-pyran in an inert solvent such as benzene and inthe presence of an acid catalyst produces the tetrahydropyran-2'-yloxy,tetrahydrofuran- 2-yloxy or 4'-methoxytetrahydropyran-4-yloxyderivatives, respectively. Methyl, ethyl and cyclopentyl ethers, forexample, are prepared upon reaction of the hydroxy compound with sodiumhydride and methyl iodide, ethyl iodide and cyclopentyl bromide,respectively.

Compounds of formulas II and IV wherein R=hydroxymethyl can be convertedinto the corresponding acids (11 and IV, R=COOH) by oxidation withchromium trioxide, and the acids can be esterified by conventionalmethods, such as treatment with an excess of a diazoalkane such asdiazomethane or diazoethane in either solution.

Compounds of Formulas II and IV are converted into the 2a-monomethyl and2,2-dimethyl derivatives by reaction with a methyl halide such as methyliodide in the presence of potassium t-butoxide, using a mixture oftoluene-hexamethylphosphoramide as solvent. The reaction is carried outat a temperature below 0 C., and preferably between 10 to C., adding asolution of potassium t-butoxide in t-butanol to a previously cooledmixture of the steroid and methyl iodide intoluene-hexamethylphosphoramide.

The reaction mixture is maintained at said temperature for a period oftime of between 30 minutes and several hours, preferably between 4 and 6hours, isolating the product by conventional techniques such as bydilution with water, separtion of the organic phase and evaporation ofthe solvents under reduced pressure, or by steam distillation of thesolvents followed by extraction of the product with an organic solventnon-miscible with water such as ethyl acetate or methylene chloride.

The A starting materials for the process object of the present inventionare obtained from 3-methoxy-16,l7- secoestra-1,3,5(10)-trien-17-oic acidmethyl ester, 3-meth- 0xy-16,l7-seco-l4 3-estra-1,3,5( 10)-trien-17-oicacid methyl ester and the corresponding 18-alkyl derivatives thereof(16,17-seco-13-alkyl gonatrienes) in accordance with our copendingapplication Ser. No. 142,763, filed on even date herewith and entitled16,17-Seco-A and -A Steroids.

Briefly, the methods for producing the same are as follows:

16,17-secoestr-5(10)-en-17-ol-3-one is obtained from3-methoxy-16,17-secoestra-l,3,5(10)-trien-17-ol.

The latter, upon reduction of the aromatic ring under Birch conditions,i.e. using an alkali metal such as lithium in liquid ammonia, followedby hydrolysis of the 3-methoxy-2,5(10)-diene intermediate with oxalicacid in aqueous methanol furnishes the desired 16,17-secoestr-5(10)-en-17-ol-3-one. Alternatively, the Birch reduction can be performed on the17-oic acid followed by reduction to the 17-01 or on the 17-oic acidmethyl ester to furnish the 17- 01 compound.

Oxidation of 16,17-secoestr-5(l0)-en-17-ol-3-one with 8N chromiumtrioxide in sulfuric acid or chromium trioxide in pyridine gives rise to3-keto-16,17-secoestr-5(10)- en-17-oic acid, which in turn is esterifiedby reaction with an excess of a diazoalkane.

When a 3-methoxy-17-keto-17-alkyl-16,17-sec0estra-1,3, 5(10)-triene istreated with phenyl lithium in tetrahydrofuran solution or withphenylmagnesium bromide in ether solution, at reflux temperature, thereis obtained the 3-methoxy 17hydroxy-l7-alkyl-l7-phenyl-16,17-secoestra-1,3,5 10) -triene compound.

Reduction of a 3-methoxy 17 keto-17-alkyl-l6,l7-secoestra-l,3,5'(10)-triene with an alkali metal in liquid ammoniafollowed by mild hydrolysis of the A diene produced, i.e., using oxalicacid in aqueous methanol affords the corresponding17-hydroxy-17-alkyl-16,17- secoestr-S (10)-en-3-one compound.

Similarly, by reduction of the 17-trisubstituted compounds, i.e.,3-methoxy-17-hydrox'y-17,17-dialkyl-l6,l7- secoestra-1,3,5(10)-trienecompounds and 3-methoxy-17- hydroxy-17-alkyl-l7-pheny1 16,17secoestra-1,3,5 (l)- triene compound with an alkali metal in liquidammonia followed by hydrolysis with oxalic acid the correspond ing17-hydroxy 17,17 dialky1-1'6,l7-secoestr-5 (10)-en- 3-one and17-hydroxy-17-alkyl-17-phenyl-16,17-secoestr- 5 ()-en-3-one compoundsare produced.

17-Acetyl 16,17 secoestr-5(10)-en-3-one is obtained by oxidation of17-hydroxy-17-methyl-16,17 -secoestr- 5(10)-en-3-one with chromiumtrioxide in pyridine.

Oxidation of 3-methoxy 16,17 secoestra-1,3,5(10)- trien-17-ol withchrominum trioxide in pyridine or with a 8N solution of chromic acid inacetone and in the presence of sulfuric acid (Jones reagent) gives riseto the corresponding 3-methoxy-16,17-secoestra-1,3,5(10)- trien-17-alwhich is then reduced by chemical or electrochemical methods to thecorresponding 17-unsubstituted compound, i.e. 3-methoxy 16,17secoestra-1,3,5(10)- triene.

The 17-unsubstituted compound is then converted into16,17-secoestr-S(10)-en-3-one by reduction under Birch conditionsfollowed by hydrolysis with oxalic acid.

Similarly, electrochemical or chemical carbonyl reduc tion of a3-methoxy-17-keto-17-alkyl46,17-secoestra-1,3, 5(10)-triene compounde.g. 3-methoxy 17 keto-17- methyl-16,l7-secoestra-1,3,5(10)-trieneproduces the corresponding compounds substituted at C-17 by an alkylgroup e.g. 3 methoxy-17-methyl 16,17 secoestra-1,3, 5(10)--triene, whichin turn is reduced with an alkaline metal in liquid ammonia and the 2,5(10)-diene intermediate hydrolyzed with oxalic acid to afford thecorresponding 17-alkyl 16 ,17 secoestr-5(10)-en-3-one e.g. 17-methyl16,17 secoestr-5(10)-en-3-one. Chemical carbonyl reduction can beaccomplished by, for example, a Wollf-Kishner reduction, a Clemmensenreduction, or thioketal formation followed by treatment with Raneynickel.

The 14,8-isomers of the above mentioned compounds as well as the18-alkylated derivatives (13-alkyl-gon-5 (10)-cues) are obtained in asimilar manner, starting from 3 methoxy 16,l7-seco-14B-estra-1,3,5(10)-trien- 17-oic acid methyl ester, a 3-methoxy-13-alkyl-16,17-secogona-l,3,5(10)-trien-l7-oic methyl ester or the 14pisomers of thelast mentioned compounds.

3 Methoxy-16,17-seco-l4o-estra-1,3,5(10)-trien-l7-oic acid methyl esterand the 18-alkyl derivatives thereof are in turn obtained from14B-estrone or an l8-alkyl derivative thereof, by conversion into theenol acetate, treatment of the latter compound with osmium tetroxidefollowed by decomposition of the osmate ester with sodium bisullite togive the 16u-hydroxy-3-methoxy-14B-estra-1,3, 5(10)-trien-l7-one(16u-hydroxy-14flestr0ne) or an 18- alkyl derivative, which uponreaction with 1.1 molar equivalents of periodic acid in aqueous pyridineaffords a 3 methoxy-l6-hydroxy-17-oxa-l7a-keto-D-homo-1'4fiestratrieneor the IS-substituted derivative. Treatment of the lactol thus obtainedwith an excess of an ethereal solution of diazomethane or with methyliodide in methanol gives rise to 3 methoxy-16,17-seco-145-estra-l,3,5(10)-trien-16-aldehyde-17-oic acid methyl ester which is 'reduced bychemical or electrochemical methods to 3- methoxy16,17-seco-14fi-estra-1,3,5 (10)-trien-17-0ic acid methyl ester or thecorresponding gonatriene compound. Particularly, the elimination of thealdehyde group is carried out by converting said group into the benzylthio acetal upon reaction with benylz mercaptan in ether and in thepresence of boron trifluoride etherate, followed by desulfurization withRaney nickel.

The following Examples illustrate but are not intended to limit thescope of the present invention.

Preparation 1 Part A.A mixture of 300 g. of potassium hydroxide and 45ml. of water is heated to 260 C. in a nickel crucible, 10 g. ofestradiol are added and the temperature is then raised to 290-300 C.,maintaining this temperature during 45 minutes. At the end of this time,the foaming mass formed is allowed to cool to room temperature, water isadded and the reaction mixture let stand at said temperature overnightso the excess of potassium hydroxide dissolved. The aqueous solution isfiltered through Celite, (diatomaceous earth), and the filtrate is madeacidic by the addition of an excess of concentrated hydrochloric acid.The precipitate which forms is collected by filtration, washed withwater and air dried, to produce 16,17secoestra-1,3,5(10)-trien-3-ol-l7-oic acid (trans doisynolic acid).

Part B.A solution of 42 g. of 16,17-secoestra-1,3,5(10)-trien-3-ol-17-oic acid in 400 ml. of ethanol is heated to 30-40 C.and treated in an alternative manner with 240 ml. of dimethylsulfate in240 ml. of methanol and 40% aqueous potassium hydroxide solution, insuch a way that the pH of the reaction mixture is maintained alkaline.

After the addition, the reaction mixture is stirred at the sametemperature for 2 hours further, water is added and the productextracted with methylene chloride, the organic extract is washed withwater to neutral, dried and evaporated to dryness. The solid residue ispurified by filtration through 210 g. of Florisil, using hexane aseluant, thus yelding 3 methoxy-16,17-secoestra-1,3,5(10)-trien- 17-oicacid methyl ester.

Part C.-A solution of 18 g. of 3 methoxy 17-carbomethoxy 16,17 secoestra1,3,5(10)-triene in 200 ml. of anhydrous tetrahydrofuran is addeddropwise, under stirring to 18 g. of lithium aluminum hydride in 300 ml.of anhydrous tetrahydrofuran and the reaction mixture is refluxed for 3hours. The reaction mixture is then cooled and the excess reagentdestroyed by careful addition of saturated solution of sodium sulfateand solid sodium sulfate. The resulting mixture is filtered throughCelite diatomaceous earth and the filtrate extracted several times withmethylene chloride; the combined organic extracts are washed to neutral,dried over sodium sulfate and evaporated to dryness. Chromatography ofthe residue on silica gel, using hexanezethyl acetate (60:40) as eluantaifords 3 methoxy 16,17 secoestra 1,3,5(10)-triene- 17-ol.

Part D.A solution of 16.5 g. of 3 methoxy 16,17- secoestra 1,3,5(l0)trien 17 01 in 500 ml. of anhydrous tetrahydrofuran is added in a steadystream to 1.5 liters of liquid ammonia. To the resulting stirredsolution are added 16.5 g. of lithium in portions, and the resultingblue solution is stirred for 1 hour further. Methanol is then addeddropwise until the blue color is discharged and the ammonia is allowedto evaporate. The product is then extracted with ethyl acetate and thecombined oragnic extracts washed with water to neutral, dried oversodium sulfate and evaporated to dryness under reduced pressure, to give3 methoxy 16,17 secoestra-2,5-(10)-diene- 17-ol.

Part E.--A solution of 15 g. of 3 methoxy 16,17- secoestra 2,5 10) dien17 01 in 1280 ml. of methanol is treated with 19.5 g. of oxalic aciddissolved in 250 m1. of water. The reaction mixture is kept at roomtemperature for 45 minutes, diluted with ice water and extracted withmethylene chloride. The organic extracts are washed with sodiumbicarbonate solution and water to neutrality, dried over sodium sulfateand evaporated to dryness under vacuo. Crystallization of the residuefrom acetone-hexane affords 16,17 secoestr-(10) en 17 ol 3- one.

By the same methods starting from 18 methyl estradiol and 18-ethylestradiol, there are obtained as final products 13 ethyl 16,17 secogon5(10) en 17-01- 3-one and 13 n propyl 16,17 secogon 5(10)-e11-17-ol-3-one, respectively.

Preparation 2 A solution of 16 g. of 3-methoxy-16,l7-secoestra-1,3,5(10)-trien-17-oic acid methyl ester in 250 ml. of anhydroustetrahydrofuran is treated with an excess (approximately 200 ml.) of 4Nmethylmagnesium bromide in ether and the mixture is refluxed with theexclusion of moisture for 18 hours. The cooled mixture is cautiouslytreated with excess aqueous ammonium chloride solution and the productisolated by extraction with methylene chloride. The extract is Washedwith Water, dried over sodium sulfate and evaporated to dryness. Theresidue is purified by t.l.c. using a mixture of hexanezethyl acetate(95:5) to produce 3-methoxy-l7-methyl-16,17-secoestra- 1,3,5()-trien-17-one and 3-methoxy l7, l7-dimethyl-16, 17-secoestra-1 ,3,5(10) -trien-l7-ol.

By the same method but using 3-methoxy-13-ethyl-16, 17-secogona-l,3,5(10)-trien-l7-oic acid methyl ester and 3methoxy-13-n-propyl-l6,l7-secongona-l,3,5(10)-trienl7-oic acid methylester as starting materials, there are obtained respectively3-methoxy-13-ethyl-l7-methyl-16, l7-secogona-l,3,5 (10)-trien-17-one and3-methoxy-13- ethyl 17,l7-dimethyl-16,17-secogona-1,3,5(10)-trien-17-01; and 3-methoxy-13-n-propyl-17-methyl 16,17-secogona- 1,3,5(10)-trien-17-one and 3-methoxy-13-n-propyl-17,17-dimethyl-l6,17-secogona-1,3,5( 10)-trien-17-ol.

T he 17-methyl and 17,17-dimethyl compounds thus obtained are treated inaccordance with the methods of Parts D and E of Preparation 1, toproduce respectively:

17-methyl-16,17-secoestr-5(10)-en-17-ol-3-one,17,17-dimethyl-16,17-secoestr-5(10)-en-17-ol-3-one,13-ethyl-17-methyl-16,l7-secogon-5'(10)-en-l7-ol-3-one,l3-ethyl-l7,17-dimethyl-16,17-secogon-5(10)-en-17-ol- 3-one,13-n-propy1-17-methyl-16,17-secogon-5(10)-en=17-ol- 3-one, and13-n-propyl 17,l7-dimethyl-16,17-secogon-5(10)-en- 17-01-3 -one.

Preparation 3 Part A.-A solution of 10 g. of 3-methoxy-16,17-secoestra-1,3,5(10)-trien-17-ol in 200 ml. of acetone distilled overpotassium permanganate is cooled to 10 C. and treated under anatmosphere of nitrogen and with stirring, with a solution of 8N chromicacid (prepared by mixing 26 g. of chromium trioxide with 23 ml. ofconcentrated sulfuric acid and diluting with water to 100 ml.), untilthe color of the reagent persisted in the mixture. It is stirred for 10minutes further at the same temperature and diluted with sodiumbisulfite solution and water. The product is then extracted withmethylene chloride and the organic extract washed with water, dried oversodium sulfate and evaporated under vacuum, thus aflording a crudeproduct which upon recrystallization from acetone-hexane gives3-methoxy-16, l7-secoestra-l,3,5 (10)-trien-l7-a1.

A solution of 6 g. of 3-methoxy-16,17-secoestra-1,3, 5|( 10)-trien-l7-olin 120 ml. of pyridine is added to a mixture of 6 g. of chromic trioxidein 20 ml. of pyridine. The reaction mix-ture is allowed to stand at roomtemperature for hours, diluted with ethyl acetate and filtered throughCelite diatomaceous earth. The filtrate is washed well with water, driedand evaporated to dryness to yield 3 methoxy 16,17secoestra-l,3,5(10)-trien-17-al which may be further purified byrecrystallization from acetone: hexane.

Part B.Into the cathode compartment of a divided electrolysis cellprovided with a cellulose dialysis membrane, lead electrodes (eachelectrode measuring 2 cm. x 5 cm. x 1.6 mm.) and a stirrer, is added4.15 g. of 3-methoxy-l6,l7-secoestra-l,3,5(10)-trien-17-al and a mixtureof 600 ml. of dioxane and 500 ml. of 10% aqueous sulfuric acid (byweight). To the anode compartment is added 40 ml. of the mixture ofdioxane and 10% aqueous sulfuric acid. A current density of 0.8 amps./cm. is applied for a period of six hours. The reaction mixture is thenremoved from the cell and concentrated under reduced pressure to a smallvolume which is then extracted several times with ether. The etherextracts are combined, washed with water and a 5% aqueous sodiumbicarbonate solution, dried and evaporated to dryness to furnish3-methoxy-16,l7-secoestra-1,3,5(10)-triene.

The foregoing reactions are repeated with the exception of using3-methoxy 13 ethyl-16,17-secogona-l,3, 5(10)-trien-17-ol and3-methoxy-13-n-propyl-16, l7-secogona-l,3,5(10)-trien-17-ol as startingmaterials, to yield 3 methoxy 13 ethyl-16,17-secogona-1,3,5(10)-trieneand 3-methoxy-l3-n-propyl 16,17 secogona-1,3,5(l0)- triene,respectively.

In accordance with the electrochemical reduction set forth in Part B ofthis Preparation,3-methoxy-l7-methyll6,17-secoestra-1,3,5(10)-trien-17-one and3-methoxy-l3- ethyl-l7-methyl-l6,17-secogona-1,3,5(10)-trien 17 one areconverted into the coresponding desoxy compounds, namely 3methoxy-17-methyl-16,17-secoestra-1,3,5(10)- triene and3-methoxy-13-ethyl-17-methyl-l6,17-secogonal,3,5(10)-triene.

The 17-desoxy compounds thus obtained are in turn reduced with lithiumin liquid ammonia, in accordance with Part D of Preparation 1, and the3-methoxy-A intermediates hydrolyzed with oxalic acid, as established inPart E of said Preparation to yield respectively 16,17-secoestr-5(10)-en 3 one, 13-ethyl-l6,17-secogon-5 10)- en-3-one,13-n-propyl-16,l7-secogon-5(10) en 3 one, l7-methyll 6, l7-secoestr-5 10-en-3-one and l3-ethyl-17- methyl-16, 17-secogon-5 10)-en-3-one.

Preparation 4 A solution of 2 g. of3-methoxy-17-methyl-16,17-secoestra-1,3,5(10)-trien-17-one in 250 ml. ofanhydrous tetrahydrofuran is added dropwise to a solution of 10 molarequivalents of phenyl lithium in ml. of ether with mechanical stirringand under an atmosphere of nitrogen. The mixture is then refluxed for 5hours, cooled, poured into ice water and acidified with hydrochloricacid, stirring vigorously for 1 hour. The product is then extracted withmethylene chloride and the organic extracts washed with water toneutral, dried over sodium sulfate and evaporated to dryness.Recrystallization of the residue from acetone-hexane yields 3-methoxy 17methyl-17- phenyl-l6,l7-secoestra-l,3,5(10)-trien-17-ol.

Upon reduction of 3-methoxy 17 methyl-17-phenyl-16,l7-secoestra-1,3,5(10)-trien-17-ol with lithium in liquid ammoniafollowed by hydrolysis of the A -diene intermediate with oxalic acid, inaccordance with the methods of Preparation 1, parts D and E,17-methyl-17- phenyl-16,l7-secoestr-5(10)-en-l7-ol-3-one is obtained.

In a similar manner, 3-methoxy-13-ethyl 17 methyl-16,17-secogona-l,3,5(10)-trien-l7-one and 3-methoxy-13- n-propyl 17methyl-16,17-sec0gona-l,3,5(10)-trien-l7- one are converted respectivelyinto 13-ethyl-17-methyl-17- phenyl-16, l7-secogon-5 10)-en-17-ol-3-oneand 13-n-propyl-17-methyl-l7-phenyl-16,17-secogon-5 10)-en 17 ol- 3-one.

Preparation 5 A solution of 1 g. of17-methyl-l7-hydroxy-16,17-secoestr-5(l0)-en-3-one in 20 ml. of pyridineis added to a mixture of l g. of chromium trioxide in 20 ml. ofpyridine. The reaction mixture is allowed to stand at room temperaturefor 18 hours, and then diluted with ethyl acetate and filtered throughCelite, diatomaceous earth, washing the solid with hot ethyl acetate.The combined filtrates are washed well with water, dried over sodiumsulfate and evaporated to dryness, thus producing 17-rnethyl-16,17-secoestr-5(10)-en-3,l7-dione which is purified by crystallizationfrom acetone-ether.

Likewise, 13-ethyl-17-methyl 17 hydroxy-l6,17-secogen-5(10)-en-17-o1-3-one and 13-n-propyl-l7-methyl-l7-hydroxy-16,17-secogon-5(10)-en-17-ol 3 one are converted respectivelyinto 13-ethyl-l7-methyl-16,17-secogon- 5(10)-en-3,17-dione and13-n-propyl 17 methyl-16,l7- secogon-S l) -en-3,17-dione.

Preparation 6 Preparation 2 is repeated with the exception of usingethereal ethylmagnesium bromide and n-propylmagnesium bromide asreagents instead of methylmagnesium bromide, to produce as finalproducts l7-ethyl-17-hydroxy-l6,17- secoestr-(10)-en 3 one and17,17-diethyl-17-hydroxy- 16,17-sccoestr-S()-en-3-one, and17-propyl-17-hydroxy- 16,17-secoestr-5 10)-en-3-one and 17,17dipropyl-l7-hydroxy-16,17-secoestr-5 10)-en-3-one, respectively.

Preparation 7 A mixture of 5 g. of 14fl-estrone and 3-methylether, 75ml. of isopropenyl acetate and 0.8 g. of p-toluenesulfonic acid isheated to reflux temperature and the reaction mixture is refluxed for 18hours using a water separator, at the end of which time the resultingsolution is cooled, diluted with ethyl acetate and washed with water,sodium bicarbonate solution and water to neutrality, dried over sodiumsulfate and evaporated to dryness under vacuo, to yield3-methoxy-17-acetoxy-14fi-estra-1,3,5 (10), 16-tetraene which may bepurified by crystallization from acetone-ether.

To a solution of 3 g. of 3-methoxy-17-acetoxy-14t3-estra-1,3,5(10,16-tetraene in 60 ml. of pyridine are added 4 g. ofosmium tetroxide and the reaction mixture is kept at room temperaturefor 48 hours, under stirring. Then, 8 g. of sodium bisulfite dissolvedin 120 m1. of water and 80 ml. of pyridine are added, and the mixture isstirred at room temperature for 24 hours further. The product is thenextracted with ethyl acetate, and the combined organic extracts washedwith water to neutral, dried and evaporated to dryness. The residue ispurified by t.l.c. eluting the product with hexane-ethyl acetate 75:25thus producing 3-methoxy-14l3-estra-1,3,5(10)-trien-16uo1-17-one.

A solution of 1.19 g. of 3-methoxy-14,3-estra-1,3,5(10)-trien-16a-ol-l7-one in 20 ml. of pyridine is treated, at roomtemperature with 915 mg. (one molar equivalent) of periodic acid (HiO-2H O) dissolved in 10 ml. of water. The reaction mixture is kept atroom temperature for 20 hours, and the solvent is then eliminated underreduced pressure, taking care that the temperature is maintained below30 C. The residue is extracted with ethyl acetate and the organicextracts are washed with 5% sodium bicarbonate solution, 5% sodiumthiosulfate solution and water, dried over sodium sulfate and evaporatedto dryness under vacuo, to yield 3-methoxy-l6-hydroxy- 17 oxa 17ozketo-D-bromo-145-estra-1,3,5(10)-triene, which is used for the next stepwithout further purification.

A solution of the foregoing crude lactol in 20 ml. of methylene chlorideis treated with 20 ml. of an ethereal solution of diazomethane, and themixture is kept at room temperature for one hour. The excessdiazomethane is then destroyed by adding a few drops of acetic acid, thesolvents are eliminated under vacuo and the residue is purified byt.l.c., to yield3-methoxy-16,17-seco-14B-estral,3,5(10)-trien-16-al-17-oic acid methylester.

To a solution of 1 g. of 3-methoxy-16,17-seco-14B-estra-1,3,5(10)-trien-16-al-l7-oic and methyl ester in 5 ml. of ethylether are added 0.5 ml. of benzyl mercaptan and three drops of borontrifluoride etherate, and the mixture is kept at room temperature for 20hours. It is then diluted with ether and the ethereal solution washedseveral times with 5% potassium hydroxide solution and water to neutral,dried and evaporated to dryness. The residue is dissolved in 150 ml. ofethanol, 5 g. of Raney nickel are added and the mixture is then refluxedthrough Celite diatomaceous earth and the nickel is washed well with hotethanol. The combined filtrate and washings are evaporated to dryness,and the residue purified by chromatography on Florisil, thus producing3-methoxy-16,17- seco-145-estra-l,3,5 (10)-trien-l7-oic acid methylester.

In a similar manner, starting from 3-methoxy-l3-ethyl-14B-gona-1,3,5(10)-trien-17-one, there is obtained 3- methoxy-13-ethyl16,17 seco-14B-gona-1,3,5(10)-trien-l7- oic acid methyl ester as finalproduct.

In accordance with the procedure set forth in Preparation 1, Parts C, D,and E, 3-methoxy-16,17-seco-l4fiestra-l,3,5(10)-trien-17-oic acid methylester and 3-methoxy-13-ethyl 16,17 seco-l4,8-gona-1,3,5(10)-trien-17-oic acid methyl ester are converted respectively into16,l7-seco-l4B-estr-5(10)-en-17-ol-3-one and l3-ethyl-16,17-seco-14B-gon-5 10) -en-17-o1-3-one.

Preparation 8 Preparations 2 to 6 are repeated using the 14B-isomers ofthe starting materials used therein, thus producing the correspondingMir-products thereof, e.g.

17-methyl-17-hydroxy-l6,17-seco-14fi-estr-5(10)-en-3- one,17,17-dimethyl-17-hydroxy-16,17-seco-14p-estr-5 l0) en-3-one,13-ethyl-17-methyl-17-hydroxy-16,17-seco-14B-gon- 5 (10)-en-3-one,13-ethyl-l7,17-dimethyl-17-hydroxy-16,17-seco-14/8- gon-5( 10)-en-3-one, 16,17-seco-14 3-estr-5(10)-en-3-one,13-ethyl-16,17-seco-14B-gon-5( 10) -en-3-one,17-methyl-16,17-seco-14fl-gon-5 (10)-en-3-one,17-methyl-17-phenyl-16,17-seco-14p-estr-5(10)-en-17- ol-3-one,17-methy1-16,17-seco-14fi-estr-5(10)-en-3,17-dione,17-ethyl-17-hydroxy-16,17-seco-14fi-estr-5 (10)-en-3-one and17,17-diethyl-17-hydroxy-16,17-seco-14B-estr-5 10) -en- 3-one.

Example 1 A solution of 4.3 g. of 16,17-secoestr-5(10)-en-17-o1- 3-onein ml. of pyridine is cooled to 0 C. and treated with 5.07 g. ofpyridinium perbromide hydrobromide. The reaction mixture is stirred at 0C. for 1 hour, and at room temperature for an hour further. It is thendiluted with ice water and extracted with methylene chloride. Theorganic extracts are Washed successively with dilute hydrochloric acid,water, 5%, sodium bicarbonate solution and water until neutral, driedover sodium sulfate and evaporated to dryness under reduced pressure.The crude product is purified by t.l.c. with hexanezethyl acetate 60:40to yield 16,l7-secoestra-4,9(10)-dien-l7-ol- 3-one which may becrystallized from ether-pentane.

Example 2 A mixture of 8.6 g. of 16,17-secoestra-4,9(10)-dien-17-ol-3-one, 60 ml. of pyridine and 30 ml. of acetic anhydride is keptat room temperature for 18 hours. The mixture is then poured into iceWater, and the formed precipitate collected by filtration, washed withwater, and dried. Crystallization from ether affords 17-acetoxy-16,l7-secoestra-4,9(10)-dien-3-one in pure form.

A solution of 10 g. of 17-acetoxy-16,17-secoestra- 4,9(10)-dien-3-one in600 ml. of anhydrous ethanol is cooled to -10 C. and treated dropwise,under stirring with 15 ml. of acetyl chloride. The reaction mixture isstirred at the same temperature for 35 minutes diluted with water andextracted with methylene chloride. The organic extracts are washed toneutrality, dried and evapo- 1 1 rated to dryness, thus affording17-acetoxy-l6,l7-secoestra-(10),9(11)-dien-3-one, which is used for thenext step without further purification.

To a solution of 6.25 g. of the foregoing product in 142 ml. of dioxaneare added 11.5 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and theresulting mixture is stirred at room temperature for 18 hours. It isthen diluted with methylene chloride and the solid material separated byfiltration. The filtrate is evaporated to dryness and the residuechromatographed on neutral alumina, to produce17-acetoxy-16,l7-secoestr-4,9 ,1 1-trien-3-one.

Example 3 A solution of 1.1 g. of 17-acetoxy-16,17-secoestra-4,9(10),11-trien-3-one in 50 ml. of methanol is treated with 500 mg. ofpotassium hydroxide dissolved in 1 ml. of water and the reaction mixtureis kept at room temperature for 30 minutes. It is then poured into icewater and the product extracted with ethyl acetate. The organic extractis washed with water to neutral, dried and evaporated to dryness, togive a crude compound which upon recrystallization from methylenechloride ether afiords 16,17-secoestra-4,9(10),11-trien-17-ol-3-one.

Example 4 To a cold solution of 4.5 g. of 16,17-secoestra-4,9(10)-dien-17-ol-3-one in 120 ml. of pyridine is added ml. of heptanoylchloride and the reaction mixture is allowed to stand for 18 hours atroom temperature. The reaction mixture is then concentrated to a smallvolume under vacuo, diluted with water and extracted with methylenechloride; the organic extracts are washed with water to neutrality,dried over sodium sulfate and evaporated to dryness under reducedpressure. Crystallization of the residue from acetone-hexane gives17-heptanoyloxy-16,17- secoestra-4,9(10)-dien-3-one.

To a stirred solution of 2 g. of 17-heptanoyloxy-16,l7- secoestra4,9(10) dien-3-one in 120 ml. of anhydrous ethanol cooled to ---10 C.,are added dropwise, in a 5 minutes period, 2 ml. of acetyl chloride, andthe reaction mixture is stirred for 30 minutes further at the sametemperature, taking aliquots every 10 minutes to determine theultraviolet absorption, which changes from 308 m to 240 mi. The reactionmixture is then diluted with water and the product isolated byextraction with methylene chloride. The organic extract is washed withwater to neutral, dried and evaporated to dryness under vacuo, to yield17 heptanoyloxy-16,17-secoestra 5(10),9(11)- dien-3-one.

A mixture of 780 mg. of17-heptanoyloxy-16,17-secoestra-5(10),9(l1)-dien-3-one, 17 ml. ofdioxane and 1.43 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone isstirred at room temperature for 15 hours. It is then diluted withmethylene chloride and the solid separated by filtration. The filtrateis evaporated to dryness and purified by t.l.c. using hexane:ethylacetate 70:30, thus obtaining 17-heptanoyloxy-16,17-secoestra-4,9( 10 ,11-trien-3 -one.

Example 5 In accordance with the method of Example 1, the followingcompounds are prepared:

13-ethyl-16,17-secogona-4,9(10)-dien-17-ol-3-one,13-n-propyl-l6,17-secogona-4,9( 10 -dien- 1 7-ol-3-one, 17-methyll 6,17-secoestra-4,9 10 -dienl 7-o1-3-one,17,17-dimethyl-16,17-secoestra-4,9(10)-dien-17-01- 3-one,13-ethyl-17-methyl-l6,l7-secogona-4,9(10)-dien- 17-ol-3-one,13ethyl-17,17-dimethyl-16,l7-secogona-4,9(10)-dien- 17-ol-3-one,13-n-propyl-17-methyl-16,l7-secogona-4,9( 10)-dienl7-ol-3-one,16,17-secogona-4,9(10)-dien-3-one,13-ethyl-16,17-secogona-4,9(10)-dien-3-one,

l 2 13-n-propyl-16,17-secogona-4,9( 10)-dien-3-one,17-methyl-16,17-secoestra-4,9(10)-dien-3-one,l3-ethyl-17-methyl-16,l7-secogona-4,9(10)-dien-3-one,17-methyl-17-phenyl-16,17-secoestra-4,9 10 -dien- 17-ol-3-one, 13-ethyl-17-methyl-17-phenyl-16,17-secogona-4,9( l0)- dien-17-ol-3-one,17-methyl-16,17-secoestra-4,9(10)-dien-3 ,17-dione,13-ethyl-17-methyl-16,17-secogona-4,9(10)-diene- 3 l 7-dione,13-n-propyl-l7-methyl-16,17-secogona-4,9(10)- diene-3, 17 -dione,17-ethyl-16,17-secoestra-4,9(10)-dien-17-ol-3-one,

17-propyl-16, 17-secoestra-4,9 10)-dien-17-o1-3-one,

17,17-dipropyl-16,17-secoestra-4,9( 10)-dien-l7-ol-3-one,l6,17-seco-14/3-estra-4,9( 10)-dien-17-ol-3-one,13-ethyl-16,17-sec0-14fl-gona-4,9(10)-dien-17-ol-3-one, 17-methyl-16,17-seco-14B-estra-4,9( 10)-dien-l7- ol-3-one,17,l7-dimethyl-l6,17-seco-14 3-estra-4,9(10)-dien- 17-ol-3-one, and16,17-secol4fl-estra-4,9(10)-dien-3-one, starting from the correspondingA compounds.

Example 6 In accordance with the esterification procedure of Example 2,13-ethyl-16,17-secogona-4,9(10)-dien-l7-ol-3- one, 13 n propyll6,17-secogona-4,9(10)-dien-17-ol-3- one,17-methyl-16,17-secoestra-4,9(10)-dien-17-ol-3-one, 13-ethyl 17methyl-16,17-secogona-4,9('10) dien- 17- 01 3-one,13-n-propyl-l7methyl-16,17-secogona-4,9(10)- dien-17-ol-3-one,16,l7-seco-14fi-estra-4,9(10)-dien-17-ol- 3-one,l7-ethyl-l6,l7-seco-14fl-estra-4,9(10)-dien-17-ol-3- one and17-methyl-l6,17-seco-l4p-estra-4,9(10)-dien-17- ol-3-one are convertedinto the corresponding acetates.

Example 7 A mixture of 1 g. of 17,17-dimethyl-16,17-secoestra-4,9(10)-dien-l7-ol-3-one, 2 ml. of acetic anhydride, 5 ml. of aceticacid and 1 g. of p-toluenesulfonic acid is kept at room temperature for2 hours. The reaction mixture is then diluted with water, extracted withmethylene chloride and the organic extracts washed with water, sodiumcarbonate solution and water to neutrality, dried over sodium sulfateand evaporated to dryness under vacuo. Crystallization of the residuefrom acetone-ether gives 17, 17-dimethyl-17-acetoxy-16,17-secoestra-4,9(10) -dien-3-one.

By using propionic anhydride and enanthic anhydride in place of aceticanhydride the corresponding propionate and enanthate of17,l7-dirnethyl-17-hydroxy-16,17-secoestra-4,9(10)-dien-3-one areobtained.

In a similar manner are produced the acetates, propio nates, andenanthates 0f 13-ethyl-l7,17-dimethyl-16,17- secogona4,9(10)-dien-17-ol-3-one, 17-methyl-17-phenyl-16,l7-secoestra-4,9(10)-dien-17-ol-3-one and 13-ethyl-17- methyl 17phenyl-l6,17-secogona-4,9(10)-dien-l7-ol-3- one.

Example 8 Two milliliters of dihydropyran are added to a solution of 1g. of l6,17-secoestra-4,9(10)-dien-l7-ol-3-one in 15 ml. of benzene.About 1 ml. is distilled to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane and hexane-ether :20 to yield 17 tetrahydropyran 2'yloxy-l6,17-secoestra-4,9(10)- dien-3-one.

Upon reaction of 17-tetrahydropyran-2-yloxy-16,17-secoestra-4,9(10)-dien-3-one with acetyl chloride in accordance with themethod of Example 2,17-tetrahydropyran-2'-yloxy-l6,l7-secoestra-5(10),9(11)-dien-3-one isproduced, which is converted into 17-tetrahydropyran-2'- 13yloxy-16,17-secoestra-4,9(10),1l-trien-S-one by treatment with2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

To a solution of 500 mg. of17-tetrahydropyran-2-yloxy-16,17-secoestra-4,9(10), 1l-trien-3-one in 10ml. of methanol is added 0.1 m1. of concentrated hydrochloric acid andthe reaction mixture is kept at room temperature for 3 hours. It is thendiluted with water and the formed precipitate collected by filtration,washed with water and air dried, thus obtaining16,17-secoestra-4,9(10),11-trien- 17-ol, identical to the productobtained in Example 3.

Example 9 In accordance with the method of Example 2, the 17- acetoxycompounds obtained in Example 6 are converted into the corresponding A-isomers, which upon reaction with 2,3-dichloro-5,6-dicyano-1,4benzoquinone, by following the dehydrogenation method set forth in saidExample, produce:

17-acetoxy-13-ethyl-16,17-secogona-4,9( ),11-trien- 3-one,

17-acetoxy-13-n-propyl-16,17-secogona-4,9( 10 11-trien-3-one,

17-acetoxy-17-methyl-16,17-secoestra-4,9( 10) ,1 l-trien- 3-one,

17-acetoxy-13-ethyl-17-methyl-l6,17-secogona-4,9( 10) 11-trien-3-one,

17-acetoxy-13-n-propyl-17-methyl-16,17-secogona- 4,9 10) ,11-trien-3-one, 17-acetoxy-16,17-seco-14B-estra-4,9( 10) ,11-trien-3-one,17-acetoxy-13-ethyl-16,17-seco-14fl-gona-4,9( 10) ,1 1-

trien-3-one, and 17-acetoxy-17-methyl- 1 6, 17-seco-14fi-estra-4,9 10),1 1-

trien-3-one, respectively.

The foregoing trienes are hydrolyzed to the corresponding free17-hydroxy compounds by following the method of Example 3.

Example 10 A solution of 1 g. of 16,17-secoestra-4,9(10)-dien-3- one in75 ml. of anhydrous ethanol is cooled to C. and 1.5 ml. of acetylchloride are added. The reaction mixture is stirred at the sametemperature for 1 hour, diluted with water and extracted with methylenechloride. The organic extracts are washed with water to neutral, driedand evaporated to dryness, to yield 16,17-secoestra-5(10),9(11)-dien-3-one.

To a solution of 750 mg. of 16,17-secoestra-5(10), 9(11)-diene 3 one in20 ml. of dioxane are added 1.4 g. of2,3-dichloro-3,6-dicyano-l,4-benzoquinone, and the reaction mixture isstirred at room temperature for 10 hours. It is then diluted withmethylene chloride, the hydroquinone formed filtered 01f and thefiltrate evaporated to dryness. The residue is purifiied by t.l.c. togive 16,l7-secoestra-4,9(10),11-trien-3-one.

In a simalar fashion, from the corresponding A dienes are obtained:

13-ethyl-16,17-secogona-4,9 10),11-trien-3-one,13-n-propyl-16,17-secogona-4,9( 10) ,1 1-trien-3-one,17-methyl-16,17-secoestra-4,9(10),11-trien-3-one,13-ethyl-17-methyl-16,17-secogona-4,9(10),11-trien- 3-one, 17-methyl-16,17-secoestra-4,9( 10) ,1 1-triene-3,17-dione,13-ethyl-17-methyl-16,17-secogona-4,9( 10) ,1 1-triene- 3,17-dione,13-n-propyl-16,17-secogona-4,9( 10) ,1 l-triene-S ,17-dione,

and 16,17-seco-14}8-estra-4,9(10)-dien-3-one.

Example 11 By following the method of Example 2, 17,17-dimethyl-17-acetoxy-16,17-secoestra-4,9( 10)-dien 3 one is converted into17,17-dimethyl-17 acetoxy 16,17-secoestra- 4,9( 10 11-trien-3-one.

A mixture of 1 g. of 17,17-dimethyl-l7-acetoxy-l6,17-secoestra-4,9(10),11-trien-3-one, ml. of methanol and 0.5 g. ofpotassium hydroxide dissolved in 1 m1. of water is refluxed for 1 hour.It is then neutralized with acetic acid and concentrated to a smallvolume under reduced pressure. Water is then added and the productseparated by filtration, washed with water and dried thus obtaining17,17-dimethyl 16,17 secoestra 4,9(10),11 trien-17- ol-3-one.

Example 12 In accordance with the method of Example 8, 16,17- seco 14Bestra 4,9(10),1l trien-17-o1-3-one, 13-ethyl- 16,17 secogona-4,9(10),1l-trien-17-ol-3-one, 17-methyl-16,17-secoestra-4,9(10),11-trien-17-ol-3-one and17-methyl-17-phenyl-16,17-secoestra-4,9(10)-dien-17-ol-3-one areconverted into the corresponding tetrahydropyranylethers.

Example 13 Two milliliters of dihydrofuran are added to a solution of 1g. of 16,l7-secoestra-4,9(10),11-trien-17-ol-3-one in 15 ml. of benzene.About 1 ml. is distilled to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, eluatingwith hexane, to yield 17-tetrahydrofuran 2-yloxy 16,17secoestra-4,9(10),11-trien-3-one which is recrystallized from pentane.

Similarly, l7 (4'-methoxy-tetrahydropyran-4'-yloxy)-16,17-secoestra-4,9(10),11-trien-3-one is prepared by utilization of theforegoing procedure employing 4-m'ethoxy- 5,6-dihydro-2H-pyran in lieuof dihydrofuran.

By the same method, the 17-tetrahydrofuranyl and 17-(4-methoxy-tetrahydropyranyl) ethers of the starting hydroxy compoundsof Example 12 are prepared.

Example 14 A solution of one chemical equivalent of16,17-secoestra-4,9(10),11-trien-17-ol-3-one in 30 ml. of benzene isheated to reflux and about 2 ml. removed by distillation to eliminatemoisture. The mixture is cooled to room temperature and two chemicalequivalents of sodium hydride are added, followed by the dropwiseaddition of two chemical equivalents of cyclopentyl bromide in 10 m1. ofbenzene, over a period of 20 minutes. The mixture is allowed to refluxfor 20 hours after which time the precipitate of sodium bromide isremoved by filtration and the organic phase dried and evaporated toyield 17-cyclopentyloxy-16,17-secoestra-4,9(10),11-trien-3-one which isfurther purified upon recrystallization from pentane.

Alternatively, methyl iodide and ethyl iodide can be used in lieu ofcyclopentyl bromide to producel7-methoxy-16,17-secoestra-4,9(10),11-trien-3-one and17-ethoxy-16,17-secoestra-4,9(10),11-trien-3-one respectively.

Likewise, the 7-cyclopentyl, methyl and ethyl ethers of16,17-secoestra-4,9(10)-dien-17-ol-3-one and 13-ethyl-16,17-secogona-4,9(10),11-trien-17-ol-3-one are obtained.

Example 15 A solution of 5 g. of 17-tetrahydropyran-2-yloxy-16,l7-secoestra-4,9(10),l1-trien-3-one in 100 ml. of anhydrous toluene and 50ml. of anhydrous hexamethylphosphoramide is cooled to 25 C. in a dryice-acetone bath, 6.5 ml. of methyl iodide are added and to the cooledmixture is added dropwise in a 20 minute period, a previously preparedsolution of 2 g. of potassium metal in 50 m1. of t-butanol understirring and under an atmosphere of nitrogen. The reaction mixture isstirred for 4 hours further at the same temperature, under nitrogen. Itis then diluted with water and the solvents eliminated by steamdistillation. The product is extracted with methylene chloride and theorganic extract washed with water to neutral, dried over sodium sulfateand evaporated to dryness under vacuo. The residue is dissolved inmethanol (100 ml.) containing 1 ml. of hydrochloric acid and boiled forminutes. The reaction mixture is neutralized with dilute sodiumhydroxide and evaporated to a small volume. Water is added and theproduct is isolated by extraction with methylene chloride. The residueis purified by chromatography on Florisil, to yield 2,2-dimethyl- 17acetoxy 16,17 secoestra 4,9(10),11 trien 3- one, and 2a methyl 17acetoxy 16,17 secoestra- 4,9 l0 ,1 1-trien-3-one.

A mixture of 1 g. of 2,2-dimethyl-17-hydroxy-16,17-secoestra-4,9(l0),1l-trien-3-one, 4 ml. of pyridine and 2 ml. of aceticanhydride is allowed to stand at room temperature for hours. The mixtureis then poured into ice water and the solid which forms is collected byfiltration, washed with water and dried to yield 2,2-dimethyl- 17acetoxy 16,17 secroestra 4,9(10),l1 trien- 3-one which may be furtherpurified through recrystallization from acetone hexane.

Similarly, c methyl 17 acetoxy 16,17 secoestra- 4,9(10),11-trien-3-oneis prepared.

By the same method, the following compounds are prepared from therespective starting compounds:

2,2-dimethyl-16,17-secoestra-4,9(10),11-trien-3-one,2,2-dimethyl-17-methoxy-16,17-secoestra-4,9( 10),11-

trien-3-one, 2,2,17-trimethyl-16,17-secoestra-4,9, 10 ),11-trien-3-one,2,2-dimethyl-13-ethyl-16,17-secogona-4,9(10),1 l-trien- 3-one,2,2-dimethyl-17-tetrahydropyran-2-yloxy-16,17-secoestra-4,9(10),11-trien-3-one,2,2,17,17-tetramethyl-17-acetoxy-16,17-secoestra-4,9(10),

1 1-trien-3-one, 2,2-dimethyl-17-acetoxy-16,l7-seco-l48-estra-4,9(10),11-

trien-3-one, 2,2-dimethyl-13 -ethyl-16,17-seco-14f3-gona-4,9 (10),11-

trien-3-one, 2,2-dimethyl-16,17-seco-14 3-estra-4,9( 10),11-trien-3-one,2,2-dimethyl-17-heptanoyloxy-16,17secoestra-4,9(10)- dien-3-one,2,2,17-trimethyl-13-ethyl-16,17-secogona-4,9(10)-dien- 3-one,2,2,17-trimethyl-17-acetoxy-16,l7-secoestra-4,9(10)-dien- 3 -one,2,2,17-trimethyl-13-ethyl-16,17-secogona-4,9(10)-diene- 3,17-dione,2,2,17-trimethyl-13-n-propyl-16,17-secogona-4,9(10)- dien-3,17-dione,2,2-dimethyl-17-ethyl-17-acetoxy-16,17-secoestra-4,9( 10 dien-3 -one,2,2-dimethyl-17-propyl-17-acetoxy-16,17-secoestra- 4,9( 10 -dien-3 -one,2,2-dimethyl-17,17-dipropyl-17-acetoxy-16,17-secoestra- 4,9 1O-dien-3-one, 2,2-dimethyl-17-acetoxy-16,17-seco-14/3-estra-4,9(10)-dien-3-one, 2,2-dimethyl-13-ethyl-17-acetoxy-16,17-seco-14fl-gona-4,9(10)-dien-3-one, 2,2,17-trimethyl-17-acetoxy-16,l7-seco-14fl-estra-4,9(10)-dien-3-0ne,2,2,17,17-tetramethyl-17-acetoxy-16,17-seco-14fl-estra- 4,9 10)-dien-3-one, and 2,2-dimethyl-16, 17-seco-14fi-estra-4,9 10)-dien-3-one.

Example 16 A solution of 2 g. of 2,2-dimethyl-17-acetoxy-16,17-secoestra-4,9(1'0),11-trien-3-one in 100 ml. of methanol is treated witha solution of 500 mg. of potassium hydroxide in 5 ml. of water and thereaction mixture kept at room temperature for 1 hour. It is then dilutedwith water and extracted with ethyl acetate, the organic extract iswashed with water to neutral, dried over sodium sulfate and evaporatedto dryness under vacuo, thus producing 2,2 dimethyl 16,17 secoestra4,9(10),11 trien- 17-ol-3-one.

In a similar manner are hydrolyzed other 2,2-dimethyl- 17-acetoxycompounds obtained in Example 15, e.g. 2,2-

dimethyl 17 acetoxy 16,17 seco 14f) estra- 4,9( 10) ,1 1-trien-3-one,2,2-dimethyl-17-ethyl-17-acetoxy- 16,17-secoestra4,9(10)-dien-3-one,2,2,17-trimethyl-17- acetoxy-16,17-secoestra-4,9(10)-dien-3-one and2,2-dimethyl 17 acetoxy 16,17 seco 14 3 estra 4,9(10)- dien-3-one toproduce the corresponding l7-hydroxy compounds, i.e.2,2-dimethyl-l6,17-seco-14 3-estra-4,9( 10),1 ltrien 17 ol 3 one, 2,2dimethyl 17 ethyl 16,17- secoestra 4,9(10) dien 17 o1 3 one,2,2,17-trimethyl 16,17 secoestra 4,9(10) dien 17 ol- 3-one, and2,2-dimethyl-l6,17-seco-14fi-estra-4,9(l0)- dien-17-ol-3-one.

Example 17 The 17-hydroxy compounds obtained in Example 16 areetherified with dihydropyran and dihydrofuran, in accordance with themethods of Examples 8 and 13, to yield the correspondingtetrahydropyran-2'-yloxy and tetrahydrofuran-Z'-yloxy-derivatives.

Example 18 A solution of 2 g. of 16,17-secoestra-4,9(10),11-trien-17-o1-3-one in 40 ml. of pyridine is added to a mixture of 1 g. ofchromium trioxide in 40 ml. of pyridine. The reaction mixture is allowedto stand at room temperature for 18 hours, and then diluted with ethylacetate and filtered through Celite, diatomaceous earth, washing thesolid with hot ethyl acetate. The combined filtrates are washed wellwith 5% hydrochloric acid solution and water, dried over sodium sulfateand evaporated to dryness. The residue is purified by t.l.c., to yieldthe pure 3-keto-16,17-secoestra-4,9(10),11-trien-17-oic acid.

To a solution of 1 g. of 3-keto-16,17-secoestra- 4,9(10),11-trien-17-oicacid in 20 ml. of ether is added 20 m1. of an ethereal solution ofdiazomethane, and the mixture is kept at room temperature for 1 hour.The excess diazomethane in then destroyed by adding a few drops ofacetic acid, and the solvent eliminated under vacuo, thus obtaining3-keto-16,17-secoestra-4,9(10),11-trien-17- oic acid methyl ester.

By the same methods, 16,17-secoestra-4,9(10)-diene- 17 -'ol 3 one,13-ethyl-16,17-secogona-4,9(10),11- trien 17 ol-3-one,16,17-seco-14B-estra-4,9(10)-dien- 17-ol-13-one and2,2-dimethy1-16,17-secoestra-4,9(10),11- trien-17-ol-3-one are convertedfirst into the corresponding acids, and then into the methyl esters.

When using diazonethane in lieu of diazomethane, the ethyl esters areobtained.

Example 19 To a solution of 1 g. of 17-acetoxy-16,17-secoestra-4,9(10),11-trien-3-one in 28 ml. of anhydrous tetrahydrofuran cooled to-35 C. is added dropwise under an atmosphere of nitrogen, 8 ml. ofmethyl iodide, and the mixture is stirred for 1.5 hours at -35 to 30 C.The mixture is then treated at the same temperature with a previouslyprepared mixture of 4 g. of potassium tbutoxide, 28.5 ml. of anhydroustetrahydrofuran and 11 ml. of hexamethylphosphoramide. The reactionmixture is stirred at room temperature for an additional hour, dilutedwith water and extracted with methylene chloride. The combined organicextracts are washed with water to neutral, dried over sodium sulfate andevaporated to dryness. The residue is purified by t.l.c., usinghexaneethyl acetate, :20 as gradient to yield 2a,2fi-dimethyl-17-acetoxy-16,17-secoestra-4,9(10),11 triene 3 one and 2a methyl17-acetoxy-16,17-secoestra-4,9(10),11- trien-3-one.

17-Acetoxy16,17-secoestra-4,9(10),11-trien-3-one (200 mg.) in 560 ml. ofanhydrous tetrahydrofuran is placed under a nitrogen atmosphere with 113ml. of methyl iodide. The mixture is maintained at -35 C. (:5) while asolution of 57 g. of potassium t-butoxide, 570 ml.

of tetrahydrofuran, and 140 ml. of hexamethylphosphortriamide is addedthereto with stirring over 1.5 hours. The mixture is then allowed tostand at room temperature for one hour after which time it is pouredinto water and extracted with petroleum ether. The extracts are washedwith water and evaporated to dryness in vacuum to give 20,2fl dimethyl17-acetoxy-16,17-secoestra-4,9(10),11- trien-3-one, and 2a methyl17-acetoxy-16,17-secoestra- 4,9 10), 1 1-triene-3-one.

What is claimed is:

1. A compound selected from the group of compounds represented by thefollowing formula:

wherein R represents a hydroxylated hydrocarbon radical represented bythe formulas:

OH OH lower alkyl and the hydrolyzable hydrocarbon carboxylic acidesters thereof wherein the carboxylic acid moiety has from 1 to 12carbon atoms; I R is lower alkyl;

R and R is hydrogen or methyl, provided that 'R is methyl when R ismethyl;

Z is a carbon-carbon single bond or a carbon-carbon double bond.

2. A compound according to Claim 1 wherein the hydrogeen atom at -14 isin fl-configuration.

3. A compound according to Claim 1 wherein Z is a carbon-carbon singlebond.

4. A compound according to Claim 1 wherein Z is a carbon-carbon doublebond.

5. A compound according to Claim 1 wherein the hydrogen atom at 0-14 isin a configuration.

6. A compound according to Claim 5 wherein R is hydroxymethyl or theesters thereof.

7. A compound according to Claim 5 wherein R is hydroxymethyl, R ismethyl, R and R are each hydrogen and Z is a carbon-carbon double bond,16,17- secoestra-4,9( ,1 1-trien-17-ol-3-one.

8. A compound according to Claim 5 wherein R is acetoxymethyLR ismethyl, R and R are each hydrogen and Z is a carbon-carbon double bond,17-acetoxy-16, 17-secoestra-4,9(10),1 1-trien-3-one.

9. A compound according to Claim 5 wherein R is heptanoyloxymethyl, R ismethyl, R and R are each hydrogen and Z is a carbon-carbon double bond,17- heptanolyloxy-l6,17-secoestra-4,9( 10),11-trien-3-one.

10. A compound according to Claim 5 wherein R is hydroxymethyl, R ismethyl, R and R are each hydrogen and Z is a carbon-carbon single bond,16,17-secoestra-4,9 19 )-dien-17-ol-3-one.

11. A compound according to Claim 5 wherein -R is acetoxymethyl, R ismethyl, R and R are each hydrogen and Z is a carbon-carbon single bond,17-acetoxy- 16,17-secoestra-4,9(10)-dien-3-one.

12. A compound according to Claim 5 wherein R is heptanoyloxymethyl, Ris methyl, R and R are each hydrogen and Z is a carbon-carbon singlebond, 17- heptanoyloxy-16,17-secoestra-4,9( 10) -dien-3 -one.

13. A compound according to Claim 5 wherein R is hydroxymethyl or ahydrolyzable hydrocarbon carboxylic acid ester thereof, R R and R areeach methyl and Z is a carbon-carbon double bond.

14. A compound according to Claim 5 wherein R is hydroxymethyl or ahydrolyzable hydrocarbon carboxylic acid ester thereof, R R and R areeach methyl and Z is a carbon-carbon single bond.

15. A compound according to Claim 5 wherein R is the group lower alkyl-0 0E lower alkyl in which each lower alkyl is methyl, R is methyl, Rand R are each hydrogen and Z is a carbon-carbon double bond; 17 hydroxy17,17 dimethyl-16,17-secoestra- 4,9 10)-dien-3-one.

16. A compound according to Claim 5 wherein R is the group lower alkyl0% lower alkyl in which each lower alkyl is methyl, R is methyl, R and Rare each hydrogen and Z is a carbon-carbon single bond;17-hydroxy-17,17-dimethyl-16,17-secoestra- 4,9( 10)-diene-3-one.

17. A compound according to Claim 5 wherein R is acetoxymethyl, R ismethyl, R and R are each methyl, and Z is a carbon-carbon double bond;2,2-dimethyl-17- acetoxy-l6,17-secoestra-4,9(10),11-trien-3-one.

18. A compound according to Claim 5 wherein -R is acetoxymethyl, R ismethyl, R and R are each methyl, and Z is a carbon-carbon single bond;2,2-dimethyl-17- acetoxy-16,17-secoestra-4,9( 10 -dien-3-one.

' 19. A compound according to Claim 1 wherein said compound is 17acetoxy 2a methyl-16,17-secoestra- 4,9(10),11-trien-3-one.

20. A compound according to Claim 1 wherein said compound is 2,2dimethyl-17-hydroxy-16,17secoestra- 4,9(10),11-trien-3-one.

References Cited UNITED STATES PATENTS 2,830,074 4/ 1958 Farinacchi260586 H 3,192,257 6/1965 Zderic 260586 H FOREIGN PATENTS 263,22910/1963 Australia 260586 H OTHER REFERENCES Chem. Abstracts, 61:14750h-1775lb (1964). Chem. Abstracts, 63: 13347d-13348g (1965). Chem.Abstracts, 686102 (1969).

Chem. Abstracts, 67: 91020d-91021 (1967).

VIVIAN GARNER, Primary Examiner US. Cl. X.R.

26034325, 345.9, 347.8, 404, 408, 410, 468.5, 471 R, 476 C, 482 R, 484R, 487, 488 CD, 514.5, 586 H, 600, 611 A, 611 F, 612 R; 424-299, 305,308, 309, 311, 312, 314

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,819,686 Dated June 25, 1974 InVQ fl PIERRE CRABBE et al (Page 1) It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

2 Column 1, lines 25-34, chang n Z R Column 6, line 5, change "benylz"to -benzyl--.

Column 6, line68, change "-diene-" to -dien-.-

(cont'd) F ORM PO-1050 (10-69) USCOMM-DC 6087 6-P69 t: u.s. covlmmrm'PRINTING ornc: 190 o-ais-su Patent No. 3'8l9'686 Dated June 25, 1974lnventofls) PIERRE CRABBE et al (Page 2) It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Column 9, line 72, change "and" to acid-.

Column 13, line 51, change "3,6-dicyano" to -5,6dicyano.

Column 16, line 46, change "l7-olrl3one" to l7ol3one-.

Column 17, line 40, change "hydrogeen" to hydrogen-.

Signed and sealed this 6th day of May 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officerand Trademarks FORM po'wso uscoMM-oc B0376-P69 Ls. GOVERNHENT PRINTINGDFFICE 2 l9" J6'3Jl

